In the first part of this series we introduced the concept of cell-based immunotherapy with T cell transplants. Next, we describe an even more potent approach to cancer treatment with T cells that are engineered to express anti-tumor molecules or cell surface tumor-identifying killer receptors. The latter of which are called chimeric antigen receptors, or CARs.
Chimeric antigen receptor (CAR) fusion proteins are engineered to contain an antigen-binding domain and T cell intracellular signaling domains. CAR-expressing T cells transplanted into a patient can localize to tumor sites where they recognize the target antigen. These antigen expressing tumor cells are then destroyed, making CAR-expressing T cells a potentially long-term, anti-tumor immunity-providing approach to cancer treatment.
CD19 expressing B cells have already been successfully targeted by CAR-expressing T cells in both acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). These engineered T cells are engrafted to the leukemia patients where they proliferate and generate a long-lasting arsenal of anti-tumor CARs to help prevent tumor relapse.
The Next Generation of CARs in T Cells
After the simplest first generation of CARs, second generation versions additionally expressed co-stimulatory receptors. The even more complex third generation CARs improve their anti-tumor activity seven-fold by combining several receptors and co-receptors on the T cell surface. Researchers are designing new CARs to recognize a variety of tumor cell antigens that T cells, which are conveniently available from HemaCare, can be engineered to express in order to target a wide range of cancer types. One group created TanCAR , a synthetic molecule capable of bispecific activation and T cell targeting, which can amplify the T cell response because it recognizes both tumor cells and elements of the tumor microenvironment.
By providing a targeted, specific, and lasting cancer treatment, CAR based therapy provides hope to increase efficiency and decrease the side effects of currently available options in oncology. Fortunately, the road to the clinic has already begun, with CARs receiving approval for a Phase I clinical trial where T cells are used for adoptive cell therapy. Still, much needs to be done to further our understanding of CARs in T cell therapy so we can improve the design and implementation of different approaches to control the fate of and reaction to these transferred cells .
Stay tuned for our next post where we will highlight CAR- and T cell receptor (TCR)-expressing hematopoietic stem cells (HSCs). TCRs can recognize a larger range of tumor-associated antigens, not just those on the surface of the cell, and starting with HSCs instead of T cells has additional advantages as well.
 Vonderheide, R. H., & June, C. H. (2014). Engineering T cells for cancer: our synthetic future. Immunological reviews, 257(1), 7-13.
 Karmakar, S. (2014) Cell Based Immunotherapy: As a Promising Futuristic Solution for Effective Cancer Therapy. Single-Cell Biology, 3:1.
 Zakaria, G. et al. (2013) TanCAR: A Novel Bispecific Chimeric Antigen Receptor for Cancer Immunotherapy. Molecular Therapy Nucleic Acids 2: e105.